Cytotoxic triterpenes fromCrataegus pinnatifida

Bioassay-guided fractionation of Crataegus pinnatifida (Rosaceae) gave two cytotoxic ursane-type triterpenes which were identified as uvaol (1) and ursolic acid (2) by physicochemical and spectroscopic methods. 3-Oxo-ursolic acid (3) was synthesized from ursolic acid (2) by Jones method. The cytotoxic activities of these compounds were tested against murine L1210 and human cancer cell lines (A549, SK-OV-3, SK-MEL-2, XF498, and HCT15) in vitro. Compounds 1 and 2 showed moderate cytotoxicities against L1210, whereas they showed weak activities against human cancer cell lines. However, compound 3 exhibited potent cytotoxic activities both in murine and in human cancer cell lines.     

Synthesis and cytotoxic activities of 2-alkyl-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-2,6,9-triazacyclopenta[<Emphasis Type="Italic">b</Emphasis>]anthracene-5,10-diones

A series of 2-alkyl-2,3-dihydro-1H-2,6,9-triazacyclopenta[b]anthracene-5,10-diones (4a-f) were synthesized and their in vitro cytotoxic activities were evaluated against six human cancer cell lines (HCT15, SK-OV-3, A549, SNB19, MCF7 and MCF7/ADR). A number of compounds including 4c and 4d showed 2-180 times more potent cytotoxic activity than doxorubicin against all human cancer cell lines tested. Furthermore, these compounds retained considerable cytotoxic activity against the doxorubicin-resistant cell line MCF7/ADR, implying their therapeutic potential to treat doxorubicin-resistant tumors.     

Cytotoxic and antimutagenic stilbenes from seeds of Paeonia lactiflora

Cytotoxic and antimutagenic effects of a novel cis-epsilon-viniferin and five known stilbenes, transresveratrol, trans-epsilon-viniferin, gnetin H, suffruticosols A and B, isolated from the seeds of Paeonia lactiflora Pall. (Paeoniaceae) were determined against five different cancer cell lines, and mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Salmonella typhimurium TA100, respectively. Six stilbenes showed cytotoxic activity in a dose-dependent manner, and especially did potent cytotoxic activity against C6 (mouse glioma) cancer cell with IC50 values ranging from 8.2 to 20.5 microg/ml. trans-Resveratrol showed significant cytotoxic activity against HepG2 (liver hepatoma) and HT-29 (colon) human cancer cell lines with IC50 values of 11.8 and 25.2 g/ml, respectively. In contrast, trans-epsilon-viniferin and cis--viniferin, and gnetin H exhibited marked cytotoxic activity against Hela (cervicse) and MCF-7 (breast) human cancer cell lines with IC50 values of 20.4, 21.5, and 12.9 microg/ml, respectively. However, suffruticosol A and B had less cytotoxic effect against all cancer cells except C6. Meanwhile, six stilbenes exerted antimutagenic activity in a dose-dependent fashion. Of them, trans-resveratrol exhibited the strongest antimutagenic effect against MNNG with IC50 value of 27.0 microg/plate, while other five resveratrol oligomers also did moderate antimutagenic activity with IC50 values ranging from 31.7 to 35.2 microg/plate.     

Recognition of the importance of imidazolidinone motif for cytotoxicity of 4-phenyl-1-arylsulfonylimidazolidinones using thiadiazolidine-1,1 -dioxide analogs

For probing the importance of planarity of imidazolidinone motif of 4-phenyl-1-(N-acylindoline-5-sulfonyl)imidazolidinones for their cytotoxicity, 4-phenyl-1-(N-acylindoline-5-sulfonyl)[1,2,5]thiadiazolidine-1,1-dioxides 2 were prepared and their cytotoxicity were measured against human lung carcinoma (A549), human colon carcinoma (COL0205), human ovarian cancer (SK-OV-3), human leukemic cancer (K562), and murine colon adenocarcinoma (Colon26) cell lines in vitro. Although only carbonyl moiety of imidazolidinone ring was replaced with sulfonyl group, compounds 2 do not show any activity against all five cancer cell lines unlike 1. Therefore the planarity of imidazolidinone ring of 1 should be an important factor for their cytotoxic activity.     

Cytotoxic phenolic constituents ofAcer tegmentosum maxim

The chromatographic separation of the MeOH extract from the twigs of Acer tegmentosum led to the isolation of ten phenolic compounds. The structures of these compounds were determined using spectroscopic methods as 3,7,3',4'-tetramethyl-quercetin (1), 5,3'-dihydroxy-3,7,4'-trimethoxy flavone (2), 2,6-dimethoxy-p-hydroquinone (3), (-)-catechin (4), morin-3-O-alpha-L-lyxoside (5), p-hydroxy phenylethyl-O-beta-D-glucopyranoside (6), 3,5-dimethoxy-4-hydroxy phenyl-1-O-beta-D-glucoside (7), fraxin (8), 3,5-dimethoxy-benzyl alcohol 4-O-beta-D-glucopyranoside (9) and 4-(2,3-dihydroxy propyl)-2,6-dimethoxy phenyl beta-D-glucopyranoside (10). The compounds were examined for their cytotoxic activity against five cancer cell lines. Compound 3 exhibited good cytotoxic activity against five human cancer cell lines with ED50 values ranging from 1.32 to 3.85 microM.     

Cytotoxic constituents of the octocoralDendronephthya gigantea

A known monoalkyl glycerol ether, (+/-)-1-nonadecyloxy-2,3-propanediol (1) was isolated from the ethyl acetate extract of a soft coral Dendronephthya gigantea as a weakly cytotoxic constituent against four human cancer cell lines, A549, HT-29, HT-1080, and SNU-638. In addition, a known ceramide, (2S,3R,4E,8E)-N-hexadecanoyl-2-amino-4,8-octadecadiene-1,3-diol (2), was also isolated as an inactive constituent. This is the first report on the isolation of the compounds 1 and 2 from the octocoral, Dendronephthya species.     

Potentin Vitro anticancer activity of metacycloprodigiosin and undecylprodigiosin from a sponge-derived actinomyceteSac-charopolyspora sp. nov.

Bioassay-guided fractionation of CHCl3 extract from the fermentation broth of a sponge Mycale plumose-derived actinomycete Saccharopolyspora sp. nov., led to the isolation of two known prodigiosin analogs--metacycloprodigiosin (1) and undecylprodigiosin (2). These compounds exhibited significant cytotoxic activities against five cancer cell lines: P388, HL60, A-549, BEL-7402, and SPCA4. This is the first report on the significant cytotoxicity of metacycloprodigiosin (1) against human cancer cell lines.     

Design, synthesis and in vitro cytotoxicity studies of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD)--polymade conjugates and 2,2'-PBD dimers

A series of novel pyrrolo[2,1-c][l,4]benzodiazepine (PBD)-polyamide conjugates (1 and 2) and 2,2'-PBD dimers (3, 4 and 5) were synthesized and evaluated for cytotoxicity in >60 human tumor cell lines. In general PBD-polyamide conjugates (1 and 2) exhibit higher cytotoxic potency compared with 2,2'-PBD dimers (3, 4 and 5). Compound 2 exhibits a wide spectrum of anticancer activities against 17 cell lines in six cancer panels with LC50 values of <9 microM, and is especially effective against colon cancer, melanoma, renal cancer and breast cancer. Compound 1 selectively affects cell growth against renal cancer A 498 cell line and compound 4 affects cell growth against breast cancer MDA-MB-231/ATCC cell line with an LC50 value 0.06 microM. Increases in the chain length of the linker in 2,2'-PBD dimers significantly increase the cytotoxic potency and increases in the number of pyrrole groups in the PBD-polyamide conjugates similarly increase the cytotoxic potency.     

Cytotoxic saponins from the root ofDipsacus asper wall

Cytotoxic activitiy of seven hederagenin saponins isolated from the root of Dipsacus asper were investigated in vitro against L1210, HL-60 and SK-OV-3 tumor cell lines by the MTT method. 3-O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl hederagenin (2), 3-O-beta-D-xylopyranosyl-(1-->3)-alpha-L-Rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl hederagenin (6) and 3-O-beta-D-glucopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl hederagenin (7) exhibited the potent cytotoxicity against the three tumor cell lines with IC50 values ranging from 4.7 to 8.7 microg/mL, with the exception of compound 7, which exhibited weak cytotoxic activity against SK-OV-3 (IC50 22.5 microg/mL). Other compounds did not exhibit any cytotoxic activity (IC50 > 30 microg/mL).     

Inhibition of topoisomerase I activity and efflux drug transporters’ expression by xanthohumol from hops

Xanthohumol (XN) and its related compounds were evaluated for their cytotoxicity against four different human cancer cell lines, A549 (lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), and HCT-15 (colon) using a sulforhodamine B assay. XN showed the most active cytotoxicity against the human cancer cell lines. Isoxanthohumol, 8-prenylnaringenin, and xanthohumol 4'-O-beta-D-glucopyranoside showed comparable cytotoxicity and (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside was the least cytotoxic compound. The anticancer properties of XN, the most active cytotoxic compound, were further investigated. XN showed an inhibitory effect on the activity of DNA topoisomerase I (topo I), which was measured from the relaxation of supercoiled DNA. The inhibition of topo I by XN might explain the cytotoxicity against the human cancer cell lines. Moreover, the expression of the drug efflux genes was investigated to predict the drug resistance. XN clearly decreased the mRNA levels of ABCB1 (MDR1), ABCC1 (MRP1), ABCC2 (MRP2), and ABCC3 (MRP3). These results suggest that XN has anticancer properties by inhibiting the topo I activity and it might be used in conjunction with other anticancer chemotherapeutic agents to reduce the drug resistance inhibiting the efflux drug transporters.     

Cytotoxic activities of diarylheptanoids from Alnus japonica

The diarylheptanoids (1–10) 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-β-D-glucopyranosyl(1→3)-β-D-xylopyranoside (1), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-β-D-apiofuranosyl(1→6)-β-D-glucopyranoside (2), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O-β-D-glucopyranoside (3), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane (4), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-one-5-O-β-D-glucopyranoside (5), oregonin (6), hirsutanonol (7), hirsutenone (8), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane-3-O-β-D-xylopyranoside (9), and platyphylloside (10), isolated from the bark of Alnus japonica, were analyzed for their cytotoxic activities on various human and mouse cancer cell lines. The cytotoxic activities of these ten compounds were evaluated against murine B16 melanoma, human SNU-1 gastric cancer, human SNU-354 hepatoma cancer and human SNU-C4 colorectal cell lines. The diarylheptanoids showed potent cytotoxic activities against murine B16 melanoma cells and human SNU-C1 gastric cancer cell when the cell viability was analyzed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay.     

Cytotoxic effects of sesquiterpene lactones from the flowers of<Emphasis Type="Italic">Hemisteptia lyrata</Emphasis> B

Four guaia-12,6-olide type sesquiterpene lactones, aguerin B (1), 8alpha-acetoxyzaluzanin C (2), cynaropicrin (3), and deacylcynaropicrin (4), were isolated from the flowers of Hemisteptia lyrata Bunge. It is the first report on the isolation of compounds 1-4 from Hemisteptia species. All the isolates (1-4) were examined for their cytotoxic activity against SK-OV-3, LOX-IMVI, A549, MCF-7, PC-3, and HCT-15 human cancer cell lines.     

New cytotoxic benzopyrans from the leaves ofMallotus apelta

Two new benzopyrans 6-[1'-oxo-3'(R)-hydroxy-butyl]-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (1) and 6-[1'-oxo-3'(R)-methoxy-butyl]-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (2) were isolated from the leaves of Mallotus apelta Muell.-Arg., (Euphorbiaceae). Their chemical structures were elucidated by spectroscopic analyses, especially by 1 D-, 2D-NMR and MS spectra. Compound 1 was found to have strong cytotoxic effect against two human cancer cell lines as human hepatocellular carcinoma (Hep-2, IC50: 0.49 microg/mL) and rhabdosarcoma (RD, IC50: 0.54 microg/mL), while compound 2 showed moderate activity against Hep-2 cell line (IC50, 4.22 microg/mL) by in vitro assay.     

Syntheses and Cytotoxicity Evaluation of Si lver(Ⅰ) Compounds of Propandioic Acid: Dimension Structure Analogues of Carboplatin

合成了三种与卡铂空间结构类似的丙二酸银（Ⅰ）的化合物：〔Ag2(CH2(CO2)2)〕n(1),〔Ag2{(CH2)4C(CO2)2)}〕n(2)和〔Ag2{CH3CHCH2C(CO2)2}〕n(3),并评价了它们对几种人类肿瘤细胞株的体外细胞毒性。所合成的化合物对实验用的几种肿瘤细胞株有强烈的毒性作用,而对正常人肝细胞的毒性作用则较弱,与肿瘤细胞株对比差异显著（P＜0.05）。虽然其作用机理还不清楚,但参照对铂类抗肿瘤药物的研究,本实验结果提示银的化合物也可能成为有希望的抗癌药物先导物。     

Cytotoxic activity of indole alkaloids from Alstonia macrophylla.

Thirteen indole alkaloids isolated from the root bark of Alstonia macrophylla and a semisynthetic bisindole O-acetylmacralstonine have been assessed for cytotoxic activity against two human lung cancer cell lines, MOR-P (adenocarcinoma) and COR-L23 (large cell carcinoma), using the SRB assay. Pronounced cytotoxic activity was exhibited by the bisindoles on both cell lines. This suggests that, in comparison with the corresponding monomeric indoles, at least part of both the ring systems present in the bisindoles is essential for cytotoxic activity. The potent alkaloids were further tested against a human normal cell line (breast fibroblasts) and other human cancer cell lines including StMI1 1a (melanoma), Caki-2 (renal cell carcinoma), MCF7 (breast adenocarcinoma), and LS174T (colon adenocarcinoma). The bisindoles O-acetylmacralstonine, villalstonine and macrocarpamine were found to possess pronounced activity against cancer cell lines with IC50 values in the range of 2-10 microM, with no discernible cell-type selectivity. However, O-acetylmacralstonine displayed discernibly less toxicity against the normal breast fibroblasts.     

Constitutents and the antitumor principle ofAllium victorialis var.platyphyllum

To search for cytotoxic components from Allium victorialis, MTT assays on each extract and an isolated component, gitogenin 3-O-lycotetroside, were performed against cancer cell lines. Cytotoxicities of most extract were shown to be comparatively weak, though IC50 values of CHCl3 fraction was found to be <31.3-368.4 microg/ml. From the incubated methanol extract at 36 degrees C, eleven kinds of organosulfuric flavours were predictable by GC-MS performance. The most abundant peak was revealed to be 2-vinyl-4H-1,3-dithiin (1) by its mass spectrum. Further, this extract showed significant cytotoxicities toward cancer cell lies. Silica gel column chromatography of the n-butanol fraction led to the isolation of gitogenin 3-O-lycotetroside (3) along with astragalin (4) and kaempferol 3, 4'-di-O-beta-D-glucoside (5). This steroidal saponin exhibited significant cytotoxic activities (IC50, 6.51-36.5 microg/ml) over several cancer cell lines. When compound 3 was incubated for 24 h with human intestinal bacteria, a major metabolite was produced and then isolated by silica gel column chromatography. By examining parent- and prominent ion peak in FAB-MS spectrum of the metabolite, the structure was speculated not to be any of prosapogenins of 3, suggesting that spiroketal ring were labile to the bacterial reaction. These suggest that disulfides produced secondarily are the antitumor principles.     

First total synthesis of protoapigenone and its analogues as potent cytotoxic agents

Protoapigenone (1), isolated from Thelypteris torresiana, previously showed significant cytotoxic activity against five human cancer cell lines. In a continued structure-activity relationship study, the first total synthesis and modification of 1 were achieved. All synthesized compounds and related intermediates were evaluated for cytotoxic activity against five human cancer cell lines, HepG2, Hep3B, MDA-MB-231, MCF-7, and A549. Among them, 24 showed 2.2-14.2-fold greater cytotoxicity than 1 and naphthyl A-ring analogues remarkably enhanced the activity.     

Cytotoxic agents from Terminalia arjuna

Although a number of chemicals have been isolated from Terminalia arjuna, only a few have been evaluated for their biological significance. As a part of our drug discovery programme for cytotoxic agents from Indian medicinal plants, four novel cytotoxic agents arjunic acid (1), arjungenin (2), arjunetin (3) and arjunoglucoside I (4) were isolated from the bark of T. ARJUNA. Out of the four compounds, arjunic acid (1) was significantly active against the human oral (KB), ovarian (PA 1) and liver (HepG-2 & WRL-68) cancer cell lines. Further, the most active compound arjunic acid was converted into seven semi-synthetic ester derivatives 5 - 11. 2-O-Palmitoyl arjunic acid (6) showed two times more activity, while 2, 3-di-O-acetyl-, 2-O-p-anisoyl-, 2, 3-di-O-benzoyl- and 2, 3-di-O-p-nitrobenzoyl arjunic acid (7 - 10) showed 1.7 - 2.3 times less activity than the cytotoxic drug vinblastine against the liver cancer cell lines HepG-2 and WRL-68 respectively.     

Modulation of NAD(P)H:Quinone oxidoreductase (NQO1) activity mediated by 5-arylamino-2-methyl-4,7-dioxobenzothiazoles and their cytotoxic potential

Synthesized 5-arylamino-2-methyl-4,7-dioxobenzothiazoles 3a-3o were evaluated for modulation of NAD(P)H: quinone oxidoreductase (NQO1) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 4,7-dioxobenzothiazoles affected the reduction potential by NQO1 activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 3a, 3b, 3g, 3h, 3n and 3o were considered as more potent cytotoxic agents, and comparable modulators of NQO1 activity.     

Synthesis and biological evaluation of 1-cyano-2-amino-benzimidazole derivatives as a novel class of antitumor agents

A series of 1-cyano-2-amino-benzimidazole derivatives were synthesized and evaluated for their cytotoxic activities in vitro against three human cancer cell lines (human lung carcinoma cell line: A549, human leukemia cell line: K562, and human prostate cancer cell line: PC-3). Most of these compounds showed potent activities against these tumor cell lines, especially against A549 and K562 cell lines. The preliminary structure–activity relationships of 1-cyano-2-amino-benzimidazole derivatives were also discussed. The cell cycle analysis was carried out in K562 cells and the results showed that compound 4d caused a marked increase of cells in G ₂/M phase.